1. Field Of The Invention
The invention relates to a new process for the production of R,S-2,2-dimethylcyclopropanecarboxylic acid (which is sometimes abbreviated below as R,S-2,2-DMCPCS).
2. Background Art
R,S-2,2-DMCPCS is an important intermediate product for the production of S-(+)-2,2-dimethylcyclopropanecarboxamide [abbreviated sometimes below as S-(+)-2,2-DMCPCA], in which R,S-2,2-DMCPCS is converted by resolution of racemates to the optically pure S-(+)-enantiomer and is subsequently converted via acid chloride to S-(+)-2,2-DMCPCA (see European Published Patent Appln. No. 093511). S-(+)-2,2-DMCPCA is used in turn as initial material for the production of the dehydropeptidase inhibitor cilastatin, which in treatment is administered together with penem or carbapenem antibiotics to prevent the deactivation of the antibiotics by a renal dehydropeptidase in the kidney (see European Published Patent Appln. No. 048301).
From the literature, several processes for the production of R,S-2,2-DMCPCS are known.
N. Kishner. J. Russ. Phys. Chem. Soc., 45, (1913), page 957 ff, describes a three-stage synthesis for the production of R,S-2,2-DMCPCS starting from phorone. In this process, the phorone is converted to a pyrazoline derivative in the first stage with hydrazine. The pyrazoline derivative is converted to a 2,2-dimethylcyclopropane derivative in the second stage with potassium hydroxide, in the presence of platinum. The 2,2-dimethylcyclopropane derivative is then oxidized to R,S-2,2-DMCPCS in the third stage with potassium permanganate. The drawback of this process is that the production of the intermediate pyrazoline has to be performed with the highly toxic and carcinogenic hydrazine.
E. R. Nelson et al., J. Am. Chem. Soc., 79, (1957), pages 3467 to 3469, also describes a three-stage process for the production of R,S-2,2-DMCPCS starting from 2,2-dimethylpropane-1,3-diol. In this way, the 2,2-dimethylpropane-1,3-diol is first converted with p-toluenesulfonyl chloride to the ditosylate derivative, the latter is then reacted in the second stage with potassium cyanide to the 2,2-dimethylcyclopropanenitrile, which then is hydrolyzed in the third stage to the corresponding acid. A great drawback of this process is that, in this way, large amounts of potassium tosylate accumulate for disposal as waste product and moderate yields (28 percent) are attained.
S. R. Landor et al., J. Chem. Soc. (C), (1967), page 2492 to 2500, describes a process for the production of R,S-2,2-DMCPCS starting from 2-methylbutenoic acid ethyl ester, which first is converted to the 2,2-dimethylcyclopropanecarboxylic acid ester with a sulfurylide derivative, which then is hydrolyzed to the corresponding acid. A great drawback of this process lies in the fact that the 2,2-dimethylcyclopropanecarboxylic acid ester is obtained in very poor yield (9 percent) and, thus, the total yield of the corresponding acid is still smaller. Another drawback of this process consists in the use of the expensive sulfurylide derivative.
Another process for the production of R,S-2,2-DMCPCS is described in West German Patent No. 2,751,133. In this process, first 4-chloro-4,4-dimethylbutyric acid ester is produced from a lactone derivative and the latter is cyclized in the presence of alcoholates to R,S-2,2-dimethylcyclopropanoic acid ester, which is subsequently hydrolyzed. A great drawback of this process lies in the fact that the lactone is not commercially available and has to be produced in a multistage synthesis.